Exploration of the cGAS-STING pathway in prostate cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 103-103
Author(s):  
Emma Reilly ◽  
Andrena McCavigan ◽  
Steven M. Walker ◽  
Nuala McCabe ◽  
Eileen Parkes ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Rna Sequencing ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Therapy ◽  
Integrative Analysis ◽  
Cancer Dataset ◽  
Early Prostate Cancer ◽  
Increased Risk ◽  
Sting Pathway

103 Background: Recent studies have demonstrated limited success of immune checkpoint therapies in unselected prostate cancer. We therefore assessed an immune based DNA Damage Repair Deficiency (DDRD) assay, that we have previously reported represents activation of the cGAS STING pathway, in the TCGA prostate cancer dataset to investigate the presence of targetable immune biology in prostate cancer. In addition we applied a second assay (the prostate cancer metastatic signature-PCM) that predicts the risk of metastatic recurrence for early prostate cancer, in order to assess if immune therapy could have a role in treating high risk disease. Methods: 498 samples with RNA sequencing data were scored with the PCM and DDRD assays. Integrative analysis was performed on 488 samples with RNA sequencing, promoter site methylation, somatic mutation and somatic copy number variation. Gene expression of n = 6 immune checkpoint targets was investigated with the subgroups identified using T-tests. The prevalence of immune infiltration in each subgroup was tested by applying a cut off to the leukocyte fraction. Cox proportional hazards regression analysis of 441 patients was assessed for biochemical recurrence. Results: Integrative analysis identified four patient subgroups characterised primarily by variances in copy number and genomic mutation. One of these subgroups ‘Metastatic-like DDRD’ had significantly higher PCM scores and DDRD immune scores compared to the other subgroups (p < 2E-12). This subgroup of patients showed elevated leukocyte fraction and expression of immune checkpoint genes: CD274 (PDL1), CTLA4, ICOS, IDO1, HAVCR2 (TIM3) & LAG3 (p < 2E-6). Genomic instability with amplification of 8q and a larger prevalence of somatic mutations including that of TP53 was also detected in this subgroup. These patients had an increased risk of biochemical relapse in both univariate (p < 2E-5) and multivariate (p < 0.008) analysis. Conclusions: We identified a poor prognostic subgroup, representing 17% of early prostate cancer patients that are at increased risk of developing metastatic disease and present with targetable immune biology. These patients may represent a viable target population for immune checkpoint and DNA damaging therapies in prostate cancer.

scholarly journals CaSpER: Identification, visualization and integrative analysis of CNV events in multiscale resolution using single-cell or bulk RNA sequencing data

2018 ◽  
Author(s):  
Akdes Serin Harmancı ◽  
Arif O. Harmanci ◽  
Xiaobo Zhou
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Complete Characterization ◽  
Integrative Analysis ◽  
Sequencing Data ◽  
Length Scales ◽  
Expression Levels ◽  
Genome Wide

AbstractRNA sequencing experiments generate large amounts of information about expression levels of genes. Although they are mainly used for quantifying expression levels, they contain much more biologically important information such as copy number variants (CNV). Here, we propose CaSpER, a signal processing approach for identification, visualization, and integrative analysis of focal and large-scale CNV events in multiscale resolution using either bulk or single-cell RNA sequencing data. CaSpER performs smoothing of the genome-wide RNA sequencing signal profiles in different multiscale resolutions, identifying CNV events at different length scales. CaSpER also employs a novel methodology for generation of genome-wide B-allele frequency (BAF) signal profile from the reads and utilizes it in multiscale fashion for correction of CNV calls. The shift in allelic signal is used to quantify the loss-of-heterozygosity (LOH) which is valuable for CNV identification. CaSpER uses Hidden Markov Models (HMM) to assign copy number states to regions. The multiscale nature of CaSpER enables comprehensive analysis of focal and large-scale CNVs and LOH segments. CaSpER performs well in accuracy compared to gold standard SNP genotyping arrays. In particular, analysis of single cell Glioblastoma (GBM) RNA sequencing data with CaSpER reveals novel mutually exclusive and co-occurring CNV sub-clones at different length scales. Moreover, CaSpER discovers gene expression signatures of CNV sub-clones, performs gene ontology (GO) enrichment analysis and identifies potential therapeutic targets for the sub-clones. CaSpER increases the utility of RNA-sequencing datasets and complements other tools for complete characterization and visualization of the genomic and transcriptomic landscape of single cell and bulk RNA sequencing data, especially in cancer research.

scholarly journals Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoshi Ma ◽  
Jinan Guo ◽  
Kaisheng Liu ◽  
Lipeng Chen ◽  
Dale Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number Variation ◽  
Single Cell ◽  
Rna Sequencing ◽  
Copy Number ◽  
Great Promise ◽  
Marker Genes ◽  
Cancer Management ◽  
Single Cell Rna Sequencing ◽  
Number Variation

Abstract Background The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity. Methods Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining. Results Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array. Conclusion Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.

598: Increased Risk of Newly Diagnosed Comorbidities in Prostate Cancer Patients Treated with Androgen Deprivation Therapy

2007 ◽  
Vol 177 (4S) ◽  
pp. 200-200 ◽  
Author(s):  
Andrea Gallina ◽  
Pierre I. Karakiewicz ◽  
Jochen Walz ◽  
Claudio Jeldres ◽  
Quoc-Dien Trinh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Androgen Deprivation Therapy ◽  
Androgen Deprivation ◽  
Newly Diagnosed ◽  
Increased Risk

1588: The Bicalutamide Early Prostate Cancer Program: Findings of the North American Trial at 7.7 Years' Median Follow-Up

2006 ◽  
Vol 175 (4S) ◽  
pp. 511-512
Author(s):  
David G. McLeod ◽  
Ira Klimberg ◽  
Donald Gleason ◽  
Gerald Chodak ◽  
Thomas Morris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
North American ◽  
Early Prostate Cancer ◽  
The North ◽  
Cancer Program

Early Prostate Cancer Revisited

2005 ◽  
Vol 38 (20) ◽  
pp. 50
Author(s):  
JON O. EBBERT ◽  
ERIC G. TANGALOS
Keyword(s):  
Prostate Cancer ◽  
Early Prostate Cancer

Male Osteoporosis

2013 ◽  
Vol 22 (04) ◽  
pp. 260-266 ◽  
Author(s):  
S. P. Tuck ◽  
R. M. Francis ◽  
B. C. Hanusch
Keyword(s):  
Prostate Cancer ◽  
Older Men ◽  
Good Evidence ◽  
Male Osteoporosis ◽  
Fracture Rate ◽  
Common Cause ◽  
Increased Risk ◽  
Osteoporosis In Men ◽  
Considerable Morbidity ◽  
Secondary Causes

SummaryMale osteoporosis is common and results in considerable morbidity and mortality. There are distinct differences in the normal aging of bone between the genders, which result in a lower fracture rate in men. Men who suffer from osteoporosis are much more likely than women to have secondary causes. The identification and treatment of these secondary causes, wherever possible, will result in substantial improvements in BMD. There is now evidence for use of many of the existing agents to treat osteoporosis in men. In younger hypogonadal men testosterone replacement is worth considering, but in older men especially the over sixties this is less effective and there is an increased risk of adverse cardiovascular and prostatic outcomes. Prostate cancer is an increasingly common cause, which is partially the result of the success of ADT. There is now good evidence for the use of bisphosphonates and denosumab in this group of patients. HIV, whilst not being specific to men, is an increasingly recognised cause of male osteoporosis. The reasons for this are multifactorial and some may well be attributable to the anti-retroviral therapy itself. There is emerging evidence of an increased fracture risk in HIV infected individuals. The bone loss can be prevented by the use of bisphosphonates.

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